tbuckley/cabot-search huggingface dataset:
Oncologic outcomes following post-cystectomy recurrence of bladder cancer based on metastatic site and role of salvage immunotherapy.
Authors: Seyedeh Sanam Ladi Seyedian, Chirag Doshi, Luis Santos Molina, Erika Wood, Jie Cai, Gus Miranda, Anne K. Schuckman, Hooman Djaladat, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2023)

574 Background: To evaluate how the location of bladder cancer recurrence after radical cystectomy (RC) affects survival and assess the role of salvage immunotherapy in this setting. Methods: On retrospective review of 4093 patients from our institutional IRB approved cystectomy database from January 1971 to December 2021, we identified 889 patients who underwent RC with curative intent and have been detected with recurrence of bladder cancer. Patients with urethral and ureteral recurrence were excluded. The data was then stratified based on the site of recurrence. Results: In this cohort of 889 patients (median age of 68, 77% male), the most common sites of metastases were widespread (48%), local (15%), lung (10%), bone (8%), retroperitoneal nodes (5.5%), liver (5%) and brain (1.5%) in order. With a median of 8.4 months, bone metastasis had shortest length from cystectomy to recurrence, while liver metastasis had shortest post recurrence survival (median of 4 months). For distant recurrence alone, only 33% survived past the first year. Salvage immunotherapy was administered in 8% of the patients and 47% received salvage chemotherapy. On multivariate analysis, liver metastasis (HR 2, 95%CI 1.4-2.9), widespread metastasis (HR 1.9, 95%CI 1.5-2.4), pathological staging&gt;T3 (HR 1.3, 95%CI 1.1-1.6) and nodal involvement at the time of RC (HR 1.5, 95%CI 1.2-1.7) were significantly associated with worse survival after the recurrence. Salvage immunotherapy provided a significant improvement in post-recurrence survival (HR 0.2, 95% CI 0.1-0.3). Conclusions: Liver, brain, and widespread metastases predominantly showed the lowest chance of survival past one year from recurrence; however, more than half of all patients with recurrence did not live past the first year. Salvage immunotherapy may lead to a better prognosis in recurrence post-cystectomy. [Table: see text]
Effect of RRx-001 on nephrotoxicity of cisplatin/etoposide in patients with solid tumors.
Authors: Nacer Abrouk, Pedro Cabrales, Bryan Oronsky, Scott Caroen, Tony R. Reid
Journal: Journal of Clinical Oncology (2023)

657 Background: RRx-001 is a small molecule anticancer agent that preclinically protects non-malignant tissues, but not tumors, against the cytotoxicities of chemotherapy and radiation. In a completed, multicenter Phase 2 trial, QUADRUPLE THREAT, patients with previously platinum-treated extrapulmonary small cell cancer (SCC), high-grade neuroendocrine carcinoma (HGNEC), non-small cell lung cancer (NSCLC), and genitourinary cancer (GUC) received 4 mg IV RRx-001 followed by etoposide plus cisplatin or carboplatin (EP). In addition to overall survival (OS), and progression-free survival (PFS), this study also evaluated the possible prevention of nephrotoxicity by RRx-001. Methods: 90 patients with SCC, HGNEC, NSCLC, and GUC that previously received ≥2 lines of therapy including a platinum doublet were treated with 4 mg RRx-001 IV once per week. At progression, RRx-001 was discontinued and 40 patients were re-challenged with IV etoposide 80-100 mg/m 2 (Days 1, 2, and 3) and cisplatin 60-80 mg/m 2 on Day 1 for 4-6 cycles. The co-primary endpoints were PFS and OS. For all patients, serum creatinine (Cr), blood urea nitrogen (BUN), and electrolytes were determined prior to, during and after each treatment cycle. Results: After 2 cycles of chemotherapy, no patients experienced BUN elevations above 20 mg/dL and creatinine beyond 1.5 mg/dL. After four cycles of chemotherapy, 36/40 (90%) patients experienced no elevations of BUN above 20 mg/dL and creatinine above 1.5 mg/dL and none of the patients experienced &gt; Grade 2 elevations of creatinine. 1/40 (2.5%) patients experienced Grade 3 hypomagnesemia (0 Grade 4). 3/40 (7.5%) patients were dose reduced or withdrawn from the trial due to platinum-related adverse events. No patients experienced renal-related serious adverse events (SAEs). One patient experienced a renal failure SAE, which was not drug related. The cumulative OS and PFS median of all the tumor types were 8.6 and 6.4 months, respectively. Conclusions: 20%-35% of patients develop acute kidney injury after cisplatin administration. Based on published clinical literature, approximately 33% of patients experience kidney injury just days following initial treatment (p = 0.0034, two-sided chi-square test comparing our study nephrotoxicity of 10% (4/40) in the first four cycles against 33% historical rate), and 20% of patients taking high-dose cisplatin experience severe renal dysfunction. The nephrotoxic effect of cisplatin is cumulative. In this heavily platinum-treated population, none of the patients were ineligible to receive cisplatin as scheduled because their serum creatinine levels had failed to return to &lt; or = 1.5 mg/dL. RRx-001 pretreatment did not affect the antitumor effects of EP as assessed by PFS and OS. This dose of RRx-001 warrants further evaluation as a nephroprotectant that reduces the cumulative renotoxic effects of cisplatin but not its antitumor efficacy. Clinical trial information: NCT02489903 .
Oncological outcome of intraarterial chemotherapy combined with radiotherapy compared to radical cystectomy for patients with muscle invasive bladder cancer.
Authors: Katsuyoshi Higashijima, Ikko Tomisaki, Akinori Minato, Kenichi Harada, Naohiro Fujimoto
Journal: Journal of Clinical Oncology (2023)

515 Background: Although radical cystectomy (RC) has been a standard treatment for muscle invasive bladder cancer (MIBC), some patients are unfit or refuse RC. Intraarterial chemotherapy combined with radiotherapy (IAC-RT) is one of the bladder preservation techniques, but there are a few data in patients who performed IAC-RT without salvage RC. The aim of this study was to evaluate the efficacy and tolerability of IAC-RT without RC compared to RC in patients with MIBC. Methods: We retrospectively reviewed patients with MIBC (T2-4N0M0) who had received either IAC-RT or RC in our hospital between January 1999 and December 2019. Intraarterial chemotherapy consisted of cisplatin (30mg/m 2 ) and adriamycin (20mg/m 2 ) on day 1 of each 1st, 2nd, 5th, 6th week. Concomitant radiotherapy (2 Gy/session, total 60 Gy) to whole pelvis was performed during chemotherapy. Salvage RC was not performed in all patients. Overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS) were compared between patients who received IAC-RT and RC. The prognostic factors of IAC-RT associated with OS were also investigated. Results: Forty-two and 143 patients received IAC-RT and RC, respectively. Of 42 patients who received IAC-RT, 28 (67%) and 14 (33%) were elective (refused RC) and imperative (comorbidity:7 poor PS:6 unresectable:1) cases, respectively. The patients who underwent IAC-RT were older (median; 77 vs 69 years old) and had poorer PS (≥2; 43% vs 4.9%) and shorter follow-up time (median; 21.9 vs 40.0 months) than those of RC. During follow up periods, metastasis, bladder cancer death, death of any cause was observed in 20, 19, and 27 patients with IAC-RT, 59, 55, and 49 patients with RC. In survival analyses, median OS was 38.7 months (95%CI, 16.9-74.7) with IAC-RT versus 154.0 months (95%CI, 70.6- not estimable (NE)) with RC, these OS curves were significantly different (P=0.001). There were not significant differences between two groups in DSS (median 46.5 vs not reached, P=0.06) and MFS (median 38.7 vs not reached, P=0.21). In multivariate analysis, clinical stage (≥T3; HR, 1.89; 95% CI, 1.04-3.46; P=0.04) and PS (≥2; HR, 2.24; 95% CI, 1.16-4.33; P=0.02) were suggested as risk factors associated with poor OS, however, treatment procedure (IAC-RT or RC) did not associate with OS. Forty of 42 (95%) patients with IAC-RT had any adverse events (AEs). Although grade3 AEs were observed in 21 (50%) patients, most of them were hematological AEs and Grade 4/5 AEs was not observed. Conclusions: IAC-RT was a useful and tolerable treatment option for patients with MIBC who were unfit or refused RC.
Evaluation of deep learning techniques (DL) in RNA sequencing data for the prediction of response to immune checkpoint inhibitors in patients with metastatic renal cell cancer m(RCC).
Authors: Sandra Alonso Paz, Ignacio Duran, Enrique Grande, Alvaro Pinto
Journal: Journal of Clinical Oncology (2023)

641 Background: Immune checkpoint inhibitors have become a cornerstone in the management of mRCC. However, to identify the most suitable patients for this treatment is an unmet medical need. We aimed to explore the utility of DL integrating clinical and molecular data to predict response to immunotherapy. Methods: We conducted a retrospective analysis using publicly available data from patients treated with nivolumab in the clinical trials Checkmate 009, 010 and 025. The primary objective was to assess the performance of different DL models (autoencoder and convolutional neural network (CNN)) predicting the PFS of these patients. With that scope, we followed several research lines including the creation of combined datasets with clinic and RNA sequencing and comparing the results of the DL models against the performance of traditional machine learning (ML) models. Finally, we came up with an interpretability analysis of those black-box models using LIME and SHAP values. Results: Clinical and transcriptomic data were available from 181 nivolumab-treated patients. Outcomes achieved confirmed that we can model the response for NIVOLUMAB using RNA sequencing data. (Table) However, DL models have not demonstrated to be significantly better than traditional ML methods when predicting response (p= 0.068). Deep autoencoder provided 68.9% accuracy, but the most accurate model was logistic regression classifier which achieved 86.4% of hit rate. Interpretability results revealed that most relevant genes for the decision making were related with the immune response and the regulation of kinases. Regarding interpretability, best results were achieved integrating both transcriptomic and clinical data (7 out of 10 DL and ML tested models achieved higher hit rates with combined data set. Logistic regression classifier improved its accuracy in 11%). Conclusions: The integration of clinical and molecular data could lead to more accurate predictions of outcome than any dataset by its own. However, further research is intended in the field of the DL analysis, as data codification and data structure could bias the results. The ongoing study ART (Artificial Intelligence in Renal Tumors) will address this issue prospectively. [Table: see text]
First in human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced urothelial carcinoma (UC) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations.
Authors: Benjamin Garmezy, Cesar Augusto Perez, Shumei Kato, Manish Sharma, Cheng Seok Quah, Betty Tam, Paul Severson
Journal: Journal of Clinical Oncology (2023)

TPS593 Background: FGFR1-4 gene alterations are infrequent across solid tumors though preclinical and clinical evidence indicate activating alterations drive oncogenesis and tumor growth. They can be found in up to 20% of patients with UC and up to 35% of upper tract UC. Reversible FGFRi are approved for the treatment of pts with locally advanced or metastatic urothelial carcinoma (UC) with susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib) or metastatic CCA harboring FGFR2 gene fusions or rearrangements (pemigatinib and infigratinib). A critical limitation of current clinical-stage FGFRi is the emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response, and indeed, about 70% of CCA patients pre-treated with FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irreversible, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated with disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in GLP toxicology studies and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given PO QD continuously in 28-day cycles until drug intolerance or disease progression. Part A is a dose-escalation assessing single agent KIN-3248 via a BOIN design to determine the MTD/RP2D. Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (UC, CCA, or other AMST), each driven by specified FGFR alterations—FGFRi-naïve and -pretreated pts are eligible in both parts. Enrollment criteria include ECOG PS 0-1, intact organ function, prior receipt of standard treatment or medical judgment that such is not appropriate. Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. Planned sample size is ~120 pts. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, &amp; duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. The study is actively enrolling patients in the US and globally. Clinical trial information: NCT05242822 .
EphA2 on urinary extracellular vesicles as a novel diagnostic marker for bladder cancer and its effect on the invasiveness of bladder cancer.
Authors: Eisuke Tomiyama, Kazutoshi Fujita, Taigo Kato, Koji Hatano, Atsunari Kawashima, Norio Nonomura
Journal: Journal of Clinical Oncology (2023)

539 Background: An accurate and non-invasive test for diagnosing bladder cancer (BCa) is needed. Potential diagnostic markers include cancer-specific proteins in urinary extracellular vesicles (uEVs) secreted directly from BCa. In this study, we aimed to identify a uEV-based protein biomarker for the diagnosis of BCa and develop an ELISA for clinical application. In addition, we evaluated whether the identified EV protein exerts a cancer-promoting effect on BCa. Methods: Urinary EVs were isolated by ultracentrifugation with a sucrose cushion. Shotgun proteomics (TMT-labeled LC-MS/MS) was performed on uEVs from seven patients with BCa and four healthy individuals. Biomarker candidates were selected from the identified proteins and validated with targeted proteomics (SRM/MRM) of uEVs from 49 patients with BCa and 48 individuals without BCa. In addition, we developed an ELISA, without time-consuming ultracentrifugation, for quantifying the uEV-based protein biomarker and evaluated its diagnostic performance using urine samples from 46 patients with BCa and 46 individuals without BCa. The effect of the validated EV protein on BCa was also analyzed in vitro. Results: Shotgun proteomics identified 1960 proteins, of which 13 membrane proteins were significantly upregulated in the uEVs from patients with BCa. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) showed the best diagnostic performance (ROCAUC = 0.79). We developed EV-EphA2-CD9 ELISA as a simple assay for uEV-EphA2 measurement with clinical value, which showed good diagnostic performance (sensitivity: 60.9 %, specificity: 97.8%). Furthermore, the combination of EV-EphA2-CD9 ELISA and urine cytology improved the detection of BCa (sensitivity, 80.4 %; specificity, 97.8 %), which could reduce the frequency of cystoscopy at bladder cancer diagnosis and during follow-up. In addition, we demonstrated that EphA2 promotes the proliferation, invasion, and migration of BCa cells and that EV-EphA2 promotes the invasion of BCa cells. The invasion-promoting effect of EV-EphA2 was attenuated by knockdown of Ephrin-A1, the ligand of EphA2, on BCa cells or by prior exposure of Ephrin-A1 to EV-EphA2, suggesting that the signalling pathway via Ephrin-A1 toward BCa cells was involved in the cancer-promoting effect of EV-EphA2. Conclusions: We identified uEV-EphA2 as a novel diagnostic marker for BCa and established EV-EphA2-CD9 ELISA for uEV-EphA2 quantification, which enables the non-invasive early diagnosis of BCa in clinical practice. Furthermore, we revealed that exosomal EphA2 promotes the invasion of BCa via its ligand; Ephrin-A1 on BCa cells, suggesting that these may be potential therapeutic targets.
Genomic profiling between Hispanic Americans (HA) and non-Hispanic (NHW) with advanced prostate cancer: A retrospective analysis of tissue, liquid, and germline testing.
Authors: Armaan Dhaliwal, Megan Kathleen Taylor, Aaron Bertolo, Ricardo J. Estrada-Mendizabal, Kathylynn Saboda, Denise Roe, Juan Chipollini, Ronald Heimark, Ken Batai, Alejandro Recio Boiles
Journal: Journal of Clinical Oncology (2023)

30 Background: Genomic testing through the employment of somatic and germline testing has become increasingly relevant in determining the prognosis and targeted therapies for advanced prostate cancer patients. Prostate cancer health disparities resulting in worse presentations and clinical outcomes have been observed in HA compared to NHW. Understanding the prevalence of different genomic alterations is paramount to bridge the gap between the two ethnic groups. Methods: This is a retrospective analysis of 190 metastatic prostate adenocarcinoma patients with 24.2% HA who presented to the University of Arizona Cancer Center from 2015 to 2022. Patients in both groups may have undergone more than one type of testing. Homologous recombination repair (HRR) included ATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCA/L, HDAC2, PALB2, RAD-51B/1C/51D, or 54L. Tissue-agnostic therapy approvals are dMMR, MSI-H, TMB-High, BRAF V600E, and NTRK/RET fusion. The proportion of HA and NHW was determined, and the statistical significance of the differences was reported using Chi 2 or Fisher’s Exact test. Results: 43.6%, 34.7%, and 38.9% of patients had somatic tissue, liquid, and germline testing, respectively analyzed for pathogenic variants. TMB-High &gt;10 (30% vs 3.6%, p=0.02), PD-L1 CPS&gt;5 (9.4% vs 0%, p=0.03) and TMPRSS2-ERG fusion (37.5 vs 7.8%, p=0.0009) had higher proportion in HA compared to NHW. No test showed a difference in BRCA 1/2 or another HRR deficiency actionable mutation between the two ethnicities. There were no other statistically significant differences in common mutations or variants of unknown significance among groups. Conclusions: Liquid and tissue biopsies indicated a difference in proportions for tissue-agnostic and immune-oncology therapeutic indications, being more prevalent in HA. TMPRSS2-ERG fusions have differences in PC development and progression by race and now potentially by ethnicity, as shown by our study. Our review revealed increased germline and somatic testing over time according to targeted therapies approval and guideline recommendations, although, there remains a critical need for advancing genomic sequencing efforts for underrepresented HA. The Hispanic Americans Prostate Cancer Comprehensive Genomic Profiling Study's (THAPCA-GPS) future investigations aim to delineate the pathogenetic differences between HA and NHW and may reduce healthcare disparities and improve clinical outcomes in HA patients. [Table: see text]
Patient perspectives on the impact of immune therapy on comorbid conditions in kidney cancer.
Authors: Ulka N. Vaishampayan, Michael D. Staehler, Sumanta Monty Pal, Emma Zipperer, Neil Vaishampayan, Neha Shah, Dena Battle
Journal: Journal of Clinical Oncology (2023)

640 Background: Immune based regimen has rapidly become the mainstay of frontline therapy in advanced RCC. The median survival is in the range of 48-55 months and long term remissions are feasible. The impact of the therapy on other health conditions has not been studied. The immune therapy toxicities can potentially be long lasting and life changing. With the conversion of advanced RCC to a chronic disease, awareness and management of these conditions is important. With the use of immune checkpoint therapy in the adjuvant setting has made this information even more critical. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. The comorbid conditions were collected and patient perspective on changes to any medical conditions was evaluated in the survey questionnaire. Results: Patients with metastatic disease being treated with systemic therapy were included in this survey. A total of 1062 patients responded to the survey of which 399 patients self identified as being metastatic and 289 reported to be treated with immune based systemic therapy. The table includes patient characteristics. 85% respondents were from the United States. The most common condition that developed after starting immune based therapy was thyroid dysfunction as seen in 81 patients, followed by hypertension (Htn) in 50 pts, chronic kidney disease in 23 pts, heart disease in 10 patients and diabetes mellitus (DM) in 13 pts. Immune disorders developed in 26 (10%) patients. Conclusions: There is a noteworthy incidence of medical conditions emerging as a result of immune checkpoint inhibitor therapies in RCC. This information would be a starting point for studying the long term effects of immune therapy and would lead towards development of survivorship programs for renal cancer. [Table: see text]